Polycystic ovary syndrome (PCOS) affects -7% of women, is a common cause of oligo-ovulatory infertility and diabetes, with a high economic burden. Patients with PCOS demonstrate a generalized upregulation of ovarian and adrenocortical androgen biosynthesis. In the two previous funding cycles of this competing renewal we established the epidemiology of adrenal androgen (AA) excess in PCOS, elucidated the underlying steroidogenic pathophysiology, tested the potential role of extra-adrenal defects, and began to explore the heritable and genetic aspects of AA excess. Our studies suggested that adrenocortical function in PCOS was more likely the result of inherited, rather than extra-adrenal factors, including insulin resistance. The overall unifying hypothesis of the present application is that "adrenocortical biosynthesis and/or metabolism in PCOS is highly heritable, and is modulated by specific genetic factors as a complex genetic trait". The specific aims of this proposal are to: Aim 1: a) Determine the degree of heritability of AA and cortisol (F) production and metabolism in the families of 300 women with PCOS, and b) Identify, recruit, and phenotype families ascertained through a proband with PCOS for subsequent haplotype-based analysis (see Aim 3); Aim 2: a) Determine the haplotype structure of 35 candidate genes that code for proteins involved in steroidogenesis and steroid metabolism in 310 PCOS and 290 controls; and b) test these haplotypes for association with PCOS and component phenotypes; Aim 3: Replicate any positive genotype- phenotype associations identified in Aim 2 using family-based association testing of the families recruited in Aim 1; and Aim 4: Sequence those genes showing association with PCOS or component phenotypes in both the case-control (Aim 2) and family-based (Aim 3) analyses, with the variants discovered by sequencing subsequently tested for association. The strengths of this application include: i) the high public health importance of PCOS; ii) the extensive experience and research productivity of the applicant in this area; iii) the strong multidisciplinary team assembled; iv) the preliminary data and recruitment tools established; v) the innovative genetic approaches proposed; vi) the inclusion of a replication experiment; vii) the detailed adrenocortical phenotyping proposed; and viii) the broad significance of the findings, furthering our understanding of the pathophysiology of PCOS and of steroidogenesis in general. [unreadable] [unreadable] [unreadable]